Project Summary/Abstract Major depressive disorder (MDD) is a leading cause of disability, with ~20% of individuals suffering from clinical depression during their lifetime. Depression is a heterogeneous syndrome consisting of several subtypes and abnormalities in multiple brain regions. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is limited. Thus, there is an urgent need to discover novel signaling pathways contributing to the development of depression so that better diagnostic tests, treatments, and preventive measures can be attained. A recent ground breaking report revealed SIRT1 as one of the first two genes successfully linked to MDD in a genome-wide study. SIRT1, a member of the sirtuin family, is characterized as a Class III histone deacetylase (HDAC), which regulates the acetylation state of histones and non-histone proteins and thereby influences gene expression and cellular physiology. Preliminary data from our lab show that chronic social defeat stress (CSDS), an ethologically validated model of depression and other stress-related disorders, regulates SIRT1 levels in the NAc, a key brain reward region. Additionally we demonstrate that SIRT1 overexpression in the NAc increases anxiety and despair-like behaviors. What is not understood is how SIRT1 influences anxiety and despair-like behaviors in a cell and circuit-specific manner. This is of particular importance due to the opposing role of D1 medium spiny neurons (MSNs) and D2 MSNs in reward- and depression-related behaviors. A central hypothesis of this project is that SIRT1 signaling acts through the D1 pathway to mediate anxiety- and despair-like behaviors. To test this hypothesis, first we will use Cre-inducible RiboTag (RT) mice, which have been crossed with D1-Cre and D2- Cre bacterial artificial chromosome (BAC) transgenic mice, allowing for the cell-type specific isolation of mRNA from D1 or D2 MSNs. Following CSDS we will measure SIRT1 mRNA from D1 and D2 MSN isolated from RiboTag-D1 Cre and RiboTag-D2 Cre mice. Second, to determine through which MSN subtype SIRT1 acts to mediate anxiety- and depressive- like behaviors we will selectively overexpress SIRT1 in D1 or D2 MSNs in the NAc and third we will utilize electrophysiology and morphological approaches, to uncover cell-type specific SIRT1 dependent neural circuits that mediate depression-like behaviors. If successful this study will have several positive impacts: 1) it would have identified the SIRT1-signaling pathway as a potential target in the development of urgently needed novel antidepressants; 2) it will provide additional support for the development of non-monoaminergic medications to treat depression; and 3) it will identify the neural circuit and cell-type specific mechanisms through which SIRT1 mediates depression-like behaviors.